Light is known to interact with endogenous or exogenous chemical agents in the skin or eyes, to produce photosensitization (phototoxicity or photoallergy). The objective of this study is to determine whether light-induce free radicals or active oxygen species play a role in photosensitization. Chlorpromazine (CPZ) is an antipsychotic drug that causes both phototoxic and photoallergic reactions. UV irradiation (330 nm) of CPZ in aqueous solution resulted in the homolytic cleavage of the carbon-chlorine bond to yield an aryl radical which extracted a hydrogen atom from suitable donors. CPZ photoionized when irradiated at 280 nm (but not at 330 nm) to give the CPZ cation radical. CPZ generated singlet oxygen (luminescence at 1270 nm) when photo-irradiated in benzene, hexane, and cyclohexane (strong), and methanol, and ethanol (weak) but not in aqueous solutions. CPZ sulfoxide, a major CPZ metabolite in man, generated .OH and the CPZ cation radical upon irradiation with near UV light. Halogenated salicylanilides eg. 3,3', 4', 5-tetrachlorosalicylanilide (TCSA) and 3,4'5-tribromosalicylanilide (TBSA) generated aryl radicals during photo-irradiation. Irradiation of TBSA with glutathione generated the corresponding thiyl radical, while under the same conditions TCSA abstracted hydrogen atom from the glycyl Alpha-carbon atom of the dipeptide Gly-Ala. The skin photoallergy of TBSA or TCSA may be due to reactions involving protein-derived radical intermediates. The chlorinated phenols bithionol and fentichlor also dehalogenated upon irradiation and in addition underwent photohydrolysis to yield semiquinone radicals. The aryl radical formed by photodeiodination of the anti-arrhythmic drug amiodarone readily abstracted a hydrogen atom from linoleic acid. Reaction of the resultant linoleyl radical with oxygen would initiate lipid peroxidation and provide an explanation for lipofuscin skin deposits in patients receiving this drug.